St. John’s Wort and Depression
By Joseph Pepping, PharmD
Used extensively for depression, anxiety, and sleep disorders, St. John’s wort (SJW) is the second leading herbal remedy sold in the United States; 1998 retail sales totaled more than $140 million.1 Several ancient physicians, including Hippocrates, mentioned SJW (Hypericum perforatum) in their writings. It was believed that the plant had the ability to "protect one from evil spirits." Traditional indications have included treatment of hysteria and depression, contusions, burns, neuralgia, gastroenteritis, ulcers, and menorrhagia.2,3 Most recent clinical research has focused on use in mild-to-moderate depression.2-5
SJW contains numerous biologically active constituents: hyperforin, hypericin, pseudohypericin, a broad range of flavonoids, carotenoids, and xanthone.2-5 Previous depression studies have focused on napthodianthrones, hypericin, and pseudohypericin as the markers of pharmacological activity.2,4,5 However, recent evidence suggests that hyperforin is the most pharmacologically active entity.6,7
Mechanism of Action
Hyperforin appears to be a non-competitive reuptake inhibitor of several neurotransmitters, including serotonin (5HT), dopamine (DA), norepinephrine (NE), GABA, and L-glutamate.8 It appears to be the only known antidepressant that inhibits reuptake of serotonin, norepinephrine, and dopamine to the same extent.3 By elevating intracellular Na+ in the presynaptic terminal to affect the intra/extracellular Na+ gradient, hyperforin effectively attenuates uptake of Na+ from the synaptic cleft, which is essential for neurotransmitter reuptake.8 This mechanism of action differs significantly from those of SSRIs, which bind competitively to serotonin reuptake sites.8 Hyperforin affects the Na+ transport mechanism in a dose-dependent and rate-limited fashion.8 SJW’s weak inhibitory effect on monoamine oxidase appears to be of little consequence at pharmacological doses.2,5
Two recent meta-analyses focused on well-designed randomized, double-blind, controlled trials (RDBCTs) and comparative studies.9,10 Using strictly defined criteria, both concluded that SJW was as effective as conventional antidepressants and more effective than placebo in treating mild-to-moderate depression.
A six-week RDBCT studied the effects of 800 mg/d standardized SJW extract (LoHyp-57) vs. 20 mg/d fluoxetine (Prozac®) in 149 elderly outpatients with mild-to-moderate depression as determined by ICD-10 criteria.11 Only patients suffering their first psychiatric disorder without symptoms of dementia were included. The efficacy of both regimens, as determined primarily by decreases in the Hamilton Rating Scale for Depression (HAMD) and secondarily by the Clinical Global Impression Scale (CGI) and Self-Rating Depression Scale (SDS), was found to be equivalent. Six of the 12 SJW patients who developed adverse drug reactions (ADRs) withdrew from the study, compared to eight of 17 fluoxetine patients. The relatively high incidence of ADRs may have been influenced by extensive ADR disclosure prior to informed consent. No information regarding duration of illness, previous psychotropic medication use, or concurrent disease states was included. Level II, no major limitations (See Figure 1 for an explanation of the evaluation standards and scales used in rating clinical studies.)
In a six-week, RDBCT of 209 severely depressed patients (as defined by HAMD and ICD-10 criteria), 1,800 mg/d standardized SJW extract (LI-160) appeared as effective as 150 mg/d imipramine.12 The multisite study included 38 hospitalized and 171 outpatients with a minimum of two prior severe depressive episodes of at least two weeks’ duration. Patients with psychotic symptoms, suicidal tendencies, pronounced agitation, drug or alcohol dependency, hallucinations, or delusions were excluded. A three- to five-day placebo washout period preceded the study. Patients whose HAMD scale improved more than 20% during washout were excluded (placebo responders). No other psychotropics were allowed with the exceptions of chloral hydrate for sleep disorders and lithium for patients who had been on the drug for a minimum of three months prior to the study. Neurological and psychiatric assessments and laboratory tests (CBC, LFTs, and Scr) were performed at baseline and days 7, 14, 28, and 42. HAMD ratings decreased in both groups with no statistical difference. Using the CGI scale, response rates of "good" and "very good" were recorded for 61.2% of the SJW group compared to 70.1% of the imipramine group. One SJW patient and eight imipramine patients withdrew because of side effects. Issues of concern include lack of a placebo arm (left out for ethical reasons) and a 900 mg/d arm for comparison. In addition, no mention is made of the length of illness or the types and dosages of psychotropics that patients had previously used. Discrepancies in interpretation of data and reporting of results also were found. Level II, major limitations
The first three-arm RDBCT compared 1,050 mg/d hypericum extract (STEI 300R) with 100 mg/d imipramine and placebo over eight weeks.13 The trial enrolled 263 patients with moderate depression according to ICD-10 classification and HAMD scores; strict inclusion/exclusion criteria were appropriate. Patients stopped antidepressant medications one week prior and were assessed at baseline and at weeks 1, 2, 4, 6, and 8. Change in the HAMD between baseline and week 8 was the primary outcome criterion. Secondary outcome criteria included Hamilton Rating Scale for Anxiety (HAMA), CGI, the Zung Self-Rating Depression Scale, and a quality of life scale (SF-36). The safety evaluation included adverse reaction monitoring, ECG, vital signs, and physical exams. Results of both primary and secondary outcomes showed SJW and imipramine to be comparable to each other and superior to placebo. Only SJW showed a statistically significant advantage over placebo according to confidence intervals, while imipramine had "a strong tendency toward superior efficacy over placebo,"13 probably because of a very high (> 60%) response rate in the placebo group. HAMA and CGI results were comparable. Minor adverse events were reported by 22% of SJW patients (primarily nausea), 46% of imipramine patients (primarily anticholinergic and GI symptoms) and 19% of the placebo group (comparable to the SJW group with less nausea). Although the imipramine dose is within therapeutic range, it is at the low end. The investigators stated that an "intent-to-treat" analysis was used, but this was not the case: Only 251/263 patients were included in the efficacy evaluation. No discussion of dropouts was provided. Level II, major limitations
A multicenter open SJW study noted adverse events in 2.4% of 3,250 subjects, necessitating discontinuation in 1.5%.14 The most common were GI irritation, restlessness, fatigue, and allergic reactions (0.3-0.6%). A review of controlled trials indicated that 19.8% and 35.9% of patients taking SJW and tricyclic antidepressants, respectively, reported side effects.2 Dry mouth, dizziness, constipation, hypotension, hypertension, and confusion have also been reported.2,5,14 Photosensitivity reactions in fair-skinned people have been reported, especially with IV hypericin or oral doses > 900 mg/d.2
Contraindications include ultraviolet light treatments5,15,16 and antidepressant use.
Pregnancy and Lactation
SJW should be avoided in pregnancy; animal studies show uterotonic and possible abortifacient properties.15 Amounts of active constituents secreted in breast milk are as yet unknown.
Because SJW extract increases neurotransmitter levels of 5HT, NE, DA, and GABA, there is potential for additive toxicity with conventional antidepressants,2,3,5-7 as evidenced by at least five case reports of serotonin syndrome-type reactions in elderly patients.17
In an attempt to decrease the side effects of standard antidepressants in patients who cannot tolerate therapeutic doses, some physicians are adding SJW to low doses of standard antidepressants. Close monitoring is essential.17 When switching from standard agents to SJW, or vice versa, a seven-day washout period is recommended.
Although some authorities warn against concurrent use with L-dopa and 5-HT, these warnings are based on theory; no clinical or animal evidence documents adverse effects or interactions.
SJW has been shown to lower serum levels of theophylline, cyclosporin, and indinavir to a clinically significant extent.18 Breakthrough bleeding also has occurred in women on oral contraceptives, possibly because of lower levels of ethinylestradiol.19 Lower digoxin levels could be associated with induction of an intestinal transporter glycoprotein,20 rather than with induction of CYP3A4 hepatic enzymes believed responsible for lower levels of other drugs. Although lower warfarin levels have occurred in a patient taking SJW, other reports demonstrate a consistent INR lowering in patients who begin concurrent SJW.21
Formulation and Dosage
The most commonly studied dosage of SJW for mild-to-moderate depression in adults is 300 mg of a standardized extract tid. Currently, most products are standardized to hypericin content (usually 0.3%, with hyperforin 2-4%). However, as mentioned above, current research indicates that standardization to the more pharmacologically active hyperforin (4-5%) is more appropriate.6-8 The empiric dosage of SJW for mild-to-moderate depression in adults is 300 mg of a standardized extract tid. When an extract standardized to hyperforin is used, the dose, based on clinical studies, is 30-45 mg/d in divided doses.
The author could not find any clinical studies of SJW to treat depression in children.
The standardized extracts of SJW tested in clinical trials appear to be a clinically proven alternative to current prescription antidepressants for treatment of mild-to-moderate depression. (See Table 1 for U.S product equivalents.) In one study, twice the usual dose was effective for severe depression. Recent clinical trials have demonstrated that these extracts are as effective as other antidepressants and consistently superior to placebo.9-12 Additionally, the side effect profile of SJW appears to be superior to currently approved U.S. antidepressant medications.11
|Table 1-Trials of oral glucosamine sulfate for symptoms of osteoarthritis|
|Study||Subjects||Level of Evidence||Control||Results||Limitations|
|* P = placebo; I = ibuprofen|
Available evidence supports a Grade B recommendation for short-term use of SJW for mild-to-moderate depression. Patients should be aware that there are many potential drug interactions; use should be supervised by a knowledgeable health care provider. A three-year NIH study currently underway will provide additional information regarding long-term effectiveness of SJW in the treatment of depression. Grade B
1. Blumenthal M. Herb market levels after five years of boom. HerbalGram 1999;47:64-65.
2. Upton R. St. John’s Wort Monograph. In: Upton R, ed. American Herbal Pharmacopoeia and Therapeutic Compendium. Santa Cruz, CA: American Herbal Pharmacopoeia; 1997:1-32.
3. Nathan P. The experimental and clinical pharmacology of St. John’s wort (Hypericum perforatum L.). Mol Psychiatry 1999;4:333-338.
4. Linde K, et al. St. John’s wort for depression—an overview and meta-analysis of randomised clinical trials. BMJ 1996;313:253-258.
5. St. John’s wort monograph. In: AltMedDex. Engelwood, CO: MICROMEDEX; 1999.
6. Chatterjee S, et al. Hyperforin as a possible antidepressant component of hypericum extracts. Life Sci 1998;63:499-510.
7. Laakmann G, et al. St. John’s wort in mild to moderate depression: The relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry 1998;31 (suppl 1):S54-S59.
8. Singer A, et al. Hyperforin, a major antidepressant constituent of St. John’s wort, inhibits serotonin uptake by elevating free intracellular Na+1. J Pharmacol Exp Ther 1999;290:1363-1368.
9. Josey E, Tackett R. St. John’s wort: A new alternative for depression? Int J Clin Pharm Ther 1999;37: 111-119.
10. Kim H, et al. St John’s wort for depression: A meta-analysis of well-defined clinical trials. J Nerv Ment Dis 1999;187:532-538.
11. Harrer G, et al. Comparison of equivalence between the St. John’s wort extract LoHyp-57 and fluoxetine. Arzneimittelforschung 1999;49:289-296.
12. Vorbach E, et al. Efficacy and tolerability of St. John’s wort extract LI-160 versus imipramine in patients with severe depressive episodes according to ICD-10. Pharmacopsychiatry 1997;30(suppl 2):S81-S85.
13. Philipp M, et al. St. John’s wort vs. placebo vs. imipramine for moderately depressed patients. BMJ 1999;319:1534-1538.
14. Woelk H, et al. Benefits and risks of the Hypericum extract LI 160: Drug monitoring study with 3250 patients. J Geriat Psychiatry Neurol 1994;7(suppl 1):S34-S38.
15. Brinker F. Herb Contraindications and Drug Interactions. 2nd ed. Sandy, OR: Eclectic Institute Publishing; 1998.
16. Mueller W, et al. Effect of St. John’s wort extract, LI-160, on neurotransmitter uptake systems and adrenergic receptor density. Presented at: The Second International Congress on Phytomedicine.1996; Munich, Germany.
17. Lantz M, et al. St. John’s wort and antidepressant drug interactions in the elderly. J Geriatr Psychiatry Neurol 1999;12:7-10.
18. Piscetelli SC, et al. Indinavir concentrations and St. John’s wort. Lancet 2000;355:547-548.
19. Ruschitzka F, et al. Acute heart transplant rejection due to Saint John’s wort. Lancet 2000;355:548-549.
20. De Smet PAGM, Touw DJ. Safety of St. John’s wort [letter]. Lancet 2000;355:575-576.
21. Yue Q, et al. Safety of St. John’s wort [letter]. Lancet 2000;355:576-577.